Heart and Blood Diseases

All Conditions

Nutritional and Metabolic Diseases

Substance Related Disorders

Symptoms and General Pathology

Wounds and Injuries

Heart Failure

Vascular Diseases

Metabolic Diseases

Heart Diseases

Drug-Related Side Effects and Adverse Reactions

Cardiotoxicity

Chemically-Induced Disorders

Radiation Injuries

Drugs and treatments used in cancer inducing cardiovascular and metabolic side effects

Anti-Cancer Agents

Joe-Elie Salem, MD, PhD

Stéphane Edehry, MD

Edehry Stephane, MD

Joe-Elie Salem, Md, PhD

Several Drugs used in routine care in oncology induce rare but often severe or fatal cardiovascular or metabolic side effects. This study will investigate, evaluate, report and treat the cardiovascular side effects of anticancer drugs, through a specific cardiovascular routine checkup and follow-up taking place in several Cardio-oncology programs throughout France. The different including centers will be: Assistance Publique - Hôpitaux de Paris (APHP.6: Pitié-Salpétrière, Saint Antoine and Tenon's hospitals, Paris, France).

Several anticancer and supportive care drugs used in oncology have an impact on the cardiovascular and metabolic systems, leading to a wide range of cardiovascular and metabolic disorders and side effects. Those are poorly described, due to the evolution of the anticancer pharmacopeia, and recent recognition of these adverse events. This study will investigate the potential benefits of a specialized cardio-oncology check-up and follow-up in this context.

Reporting, Evaluating, Preventing and Treating the Cardiotoxicity Induced by Anticancer Drugs During a Specific Cardio-oncology Consult and Follow up in Routine Care

Groupe Hospitalier Pitie-Salpetriere

Assistant director, clinical investigation center Paris Est

Neoplasms

Skin and Connective Tissue Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Trastuzumab

Antineoplastic Agents, Immunological

Patients with early-stage HER2-positive breast cancer who demonstrate a pathological complete response at time of surgery.

Patients with early-stage HER2-positive breast cancer who demonstrate a pathological complete response at time of surgery will be treated with HER2 targeted therapy for a total of 9 treatments every 3 weeks (or its equivalent if given weekly) including the treatment received preoperatively.

Lisa Vandermeer, MSc

Michelle Liu

Lisa Vandermeer

Sharon McGee, MD

The activity of trastuzumab in early-stage, HER2-positive breast cancer, has been demonstrated in many studies, with meta-analyses showing that in combination with a variety of chemotherapy backbones, trastuzumab reduces the risk of recurrence by nearly half, and death by a third. However, treatment with trastuzumab can result in cardiotoxicity, including heart failure, as well as the significant cost of treatment and the requirement for patients to attend the chemotherapy unit for treatment every 3 weeks for one year. Therefore there has been increasing interest in identifying which patients can safely have less treatment. The investigators therefore propose a real-world, single arm, multicentre trial evaluating 6 months of HER2 targeted therapy, for patients with early-stage, HER2 positive breast cancer, who achieve a pathological complete response (pCR) with upfront systemic chemotherapy and HER2 targeted therapy.

The activity of trastuzumab in early-stage, HER2-positive breast cancer, has been demonstrated in many studies, with meta-analyses showing that in combination with a variety of chemotherapy backbones, trastuzumab reduces the risk of recurrence by nearly half, and death by a third. However, treatment with trastuzumab can result in cardiotoxicity, including heart failure, as well as the significant cost of treatment and the requirement for patients to attend the chemotherapy unit for treatment every 3 weeks for one year. Therefore there has been increasing interest in identifying which patients can safely have less treatment. The duration of adjuvant trastuzumab in early-stage breast cancer in the majority of studies was empirically set at 12 months, which became the de facto standard of care. Neoadjuvant treatment has become the new standard of care for patients with early-stage HER2-positive disease. While patients with residual disease benefit from further alternative treatment those with a pathological complete response (pCR) have an excellent outcome and are candidates for treatment de-escalation. The investigators therefore propose a real-world, single arm, multicentre trial evaluating 6 months of HER2 targeted therapy, for patients with early-stage, HER2 positive breast cancer, who achieve a pCR with upfront systemic chemotherapy and HER2 targeted therapy.

Evaluating 6-months of HER2-targeted Therapy in Patients With HER2 Positive Early-stage Breast Cancer That Achieve a Pathological Complete Response to Neoadjuvant Systemic Therapy

A Single-arm, Multicentre, Pragmatic Trial Evaluating 6-months of HER2-targeted Therapy in Patients With HER2 Positive Early-stage Breast Cancer That Achieve a Pathological Complete Response to Neoadjuvant Systemic Therapy (REaCT-HER TIME)

Evaluating the feasibility of multiple Canadian site activation within the first year of study accrual. Achieved by the activation of at least 4 Canadian sites within 1 year of the first patient being accrued into the study.

Evaluating the number of medical oncologists at each study site who actively participate in the trial. Active participation includes approaching eligible patients for the study, as well as following up with the patients who are taking part in the study.

Enrolment of at least 50 participants across all sites within 9 months of the fourth site accruing its first participant.

Cardiac events defined as death from a cardiac or heart failure of New York Heart Association (NYHA) class III or IV, or with a decrease in the left ventricular ejection fraction of at least 10 percentage points from baseline to a value of less than 50%. Cardiac monitoring will be assessed as per physician standards

De-escalated HER2-positive treatment discontinuation and the reasons why treatment was discontinued

Health-related quality of life measure using the EuroQol-5 Dimension-5 Level (EQ-5D-5L) questionnaire.

The difference in cost between 6 months of HER2-positive therapy versus the standard 12 months of HER2-positive therapy.

Disease Free Survival (DFS), defined as the percentage of people in the trial who are alive and disease-free (no local invasive breast cancer recurrence, new local invasive breast cancer) at 3 years

Overall Survival (OS), defined as the number of people alive, with or without signs of cancer at 3 years

Ottawa Hospital Research Institute

Behaviors and Mental Disorders

Nervous System Diseases

Cognitive Dysfunction

Peripheral Nervous System Diseases

Cognition Disorders

Neurocognitive Disorders

Mental Disorders

Psychotic Disorders

Neuromuscular Diseases

Antirheumatic Agents

Hematinics

Vasodilator Agents

Respiratory System Agents

Flavonoid

Paclitaxel

Albumin-Bound Paclitaxel

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Silymarin

Liver Extracts

Antioxidants

Nitric Oxide

Protective Agents

which will receive four cycles of AC regimen (doxorubicin and cyclophosphamide; each cycle was given every 21 day)

followed by 12 cycles of paclitaxel (each cycle was given in a weekly basis) plus placebo tablets once daily.

which will receive the same regimen plus silymarin 140mg once daily.

Silymarin administration prevent the neuro-degeneration through inhibiting the activation of microglia, silymarin attenuates the activation of glial cell activation in cellular models possibly through inhibition of inducible nitric oxide synthase (iNOS) production, also reported to protect both microglia and astroglia from oxidative insults induced by peroxide in ex vivo system .

It also significantly reduces doxorubicin-pro-oxidative activity and decreases histological changes in liver and heart tissue . The hepato-protective and cardio-protective effects of silymarin may be attributed to its antioxidant capacity, its ability to prevent lipid peroxidation and its ability to increase glutathione concentration.

silymarin was reported to improve cognitive impairment in mice.

which will receive four cycles of AC regimen (doxorubicin and cyclophosphamide; each cycle was given every 21 day) followed by 12 cycles of paclitaxel (each cycle was given in a weekly basis) plus placebo tablets once daily.

Placebo

Aim of the work This study aims to evaluate the possible beneficial role of silymarin in attenuating both doxorubicin related cardiac and hepatic toxicities and paclitaxel associated peripheral neuropathy and improving cognitive impairment in patients with breast cancer.

This study will be a randomized placebo controlled parallel study. The study will be performed in accordance with the ethical standards of Helsinki declaration in 1964 and its later amendments.

Group one: (Placebo group; n=28) which will receive four cycles of AC regimen (doxorubicin and cyclophosphamide; each cycle was given every 21 day) followed by 12 cycles of paclitaxel (each cycle was given in a weekly basis) plus placebo tablets once daily.

Group two: (Silymarin group; n=28) which will receive the same regimen plus silymarin 140mg once daily

Breast cancer represents the most frequently diagnosed malignancy and the second most common cause of cancer death worldwide. In Egypt, breast cancer is the most common malignancy in women, accounting for 38.8% of cancers in this population, with the estimated number of breast cancer cases nearly 22,700 in 2020 and forecasted to be approximately 46,000 in 2050 .

Paclitaxel and doxorubicin are cytotoxic agents that are commonly used for treatment of breast cancer. Despite their effectiveness, both paclitaxel and doxorubicin are associated with cumulative and potential neurotoxicity and cardiotoxicity respectively . Paclitaxel induced peripheral neuropathy (PN) is a consequence of activation of the inflammatory cascade with subsequent increased pro-inflammatory cytokines production including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) . Moreover, paclitaxel can up-regulate matrix metalloproteinase-3 (MMP3) which plays an important role in the inflammatory and degenerative processes following nerve injury .

Oxidative stress plays a critical role in doxorubicin associated cardiotoxicity through direct cellular damage, induction of apoptosis and activation of nuclear factor- Kabba B (NF-ĸB) which in turn stimulates the production and release of inflammatory mediators .

Hepatotoxicity from doxorubicin was reported and it is likely due to direct toxic injury to the liver. Doxorubicin and its analogues are metabolized in the liver via microsomal enzymes, and production of a toxic or immunogenic intermediate may trigger liver injury with subsequent elevation of Serum aminotransferase.In addition, it was reported that, doxorubicin related hepatotoxicity is a consequence of free radical formation and oxidative stress and antioxidants may protect against doxorubicin-induced toxicity in the liver .

Although, the underlying neuro-protective mechanism of silymarin is mainly due to its capacity to inhibit oxidative stress in the brain, it also confers additional neuro-protection by influencing other pathways such as inflammatory pathways . Silymarin has been implicated in protecting neurons against oxidative stress and nitrosative stress . Silymarin was reported to exert direct effect on neuronal oxidant status .

Silymarin administration in a lipopolysaccharide induced animal model of peripheral neuropathy prevented the dopaminergic neuro-degeneration through inhibiting the activation of microglia. Other in-vitro studies revealed that, silymarin attenuates the activation of glial cell activation in cellular models possibly through inhibition of inducible nitric oxide synthase (iNOS) production . Silymarin was also reported to protect both microglia and astroglia from oxidative insults induced by peroxide in ex vivo system .

Treatment with silymarin prevents the increase in AST and creatine kinase (CK) serum activity and myocardial excitability in rats caused by doxorubicin . It also significantly reduces doxorubicin-pro-oxidative activity and decreases histological changes in liver and heart tissue . The hepato-protective and cardio-protective effects of silymarin may be attributed to its antioxidant capacity, its ability to prevent lipid peroxidation and its ability to increase glutathione concentration .

Cognitive impairment in patients with breast cancer began to appear in the literature in the 1990s, coincident with the increasing use of postoperative adjuvant chemotherapy . In two recent preclinical studies, silymarin was reported to improve cognitive impairment in mice, and these former studies suggested that silymarin may be a therapeutic agent for cognitive decline .

This study will be a randomized placebo controlled parallel study. The study will be performed in accordance with the ethical standards of Helsinki declaration in 1964 and its later amendments.

Group one: (Placebo group; n=28) which will receive four cycles of AC regimen (doxorubicin and cyclophosphamide; each cycle was given every 21 day) followed by 12 cycles of paclitaxel (each cycle was given in a weekly basis) plus placebo tablets once daily.

Group two: (Silymarin group; n=28) which will receive the same regimen plus silymarin 140mg once daily.

* Blood sample collection and biochemical assessment:

  1. N-terminal prohormone of brain naturetic peptide (NT-proBNP" ) and liver panel.
  2. myeloperoxidase (MPO)
  3. neurofilament light chain (NFL)
  4. andnuclear factor- Kabba B p65 (NF-ĸB p65) or TNF-alpha
* Clinical assessment of chemotherapy induced toxicities:
* Doxorubicin related cardiotoxicity will be assessed through - Echocardiography at baseline and after the last doxorubicin/ cyclophosphamide (AC) cycle.
* Paclitaxel induced peripheral sensory neuropathy will be done through: - The implication of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 5, 2017) for grading of neuropathy at baseline and by the end of every two paclitaxel cycles.
* The use of Neurotoxicity- 12 item questionnaire score (Ntx-12) from the validated Functional Assessment of Cancer Therapy/Gynecologic Oncology Group "FACT/GOG-Ntx-12" at baseline and by the end of every two paclitaxel cycles.
* The assessment of the severity of neuropathic pain through brief pain inventory short form "BPI-SF" worst item. Severity of neuropathic pain will be assessed at baseline and by the end of every two paclitaxel cycles.
* Cognitive impairment will be assessed using the brief assessment of impaired Cogentin questionnaire (BASIC-Q).
* Primary and secondary outcomes:

The primary outcome is the change in ejection fraction and percentage of patients with peripheral sensory neuropathy grade ≥ 2 with the variation of both 12-item neurotoxicity questionnaire (Ntx-12) total score and pain rating scale score. The secondary outcome is the changes in serum levels of the measured biological markers.

- Sample size calculation: According to the results of a previous study, the total number of subjects required to detect the cardio-protective effect of silymarin in patients with different types of cancer receiving anthracyclines containing chemotherapy was 25 patients . With 5% significance level, 80% statistical power and an attrition rate of 10%, the initial sample size required for the current study is 28 patients in each group.

-Ethical approval: The study will be approved by the Research Ethics Committee of Tanta University. The study will be registered as a clinical trial at ClinicalTrials.gov. All participants will be informed about the benefits and risks of the study. Any unexpected risks that will appear during the course of the research will be clarified to the participants and to the ethical committee on time. The data of the enrolled patients will be confidential. All enrolled patients will give their written informed consents. The study will be conducted between October 2022 and October 2024.

Role of Silymarin in Chemotherapy Toxicity and Cognition Improvement in Breast Cancer Patients

The Possible Protective Role of Silymarin Against Chemotherapy Induced Toxicities and Cognitive Impairment in Breast Cancer Patients

Doxorubicin related cardiotoxicity will be assessed through :Echocardiography at baseline, Before starting the first chemotherapy cycle (baseline), after the last AC cycle (for assessment of N-terminal prohormone of brain naturetic peptide "NT-proBNP" ) and after the last doxorubicin/ cyclophosphamide (AC) cycle.

change in percentage of patients with peripheral sensory neuropathy grade ≥ 2 with the variation of both 12-item neurotoxicity questionnaire (Ntx-12) total score and pain rating scale score.

N-terminal prohormone of brain naturetic peptide "NT-proBNP" ) liver panel myeloperoxidase (MPO) neurofilament light chain (NFL) nuclear factor- Kabba B p65 (NF-ĸB p65) or TNF-alpha

Tanta University

principal investigator

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Lymphoma

Hodgkin Disease

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

Hodgkin Lymphoma

Patients whose radiation therapy field essentially encompasses anterior mediastinum; namely, the majority of malignant lymphoma patients with mediastinal involvement.

As for consolidative RT used in patients with early-stage Hodgkin lymphoma, the RT field must essentially include the mediastinum.

Standard treatment protocol with combined chemoradiation

Shinn-Yn Lin, M.D.

Malignant anterior mediastinal tumors essentially include lymphomas and thymomas. The location of mediastinum is anatomically close to several critical organs such as heart, lung, and breasts, which might be affected meaningfully when the mediastinal region is irradiated. There have been quite a few studies investigating long-term toxicities concerning the above critical organs and risks of secondary malignancies related to treatment regimens combining chemotherapy and mediastinal radiotherapy. With the advancement of modern radiotherapy, highly conformal and intensity modulated radiotherapy have become a radiotherapeutic standard in recent years. However, most previous studies analyzed patients treated in the era of 2D techniques rather than conformal 3D plans. Almost inevitably, a large volume of the heart and lung was irradiated via the 2D technique with which substantial dose levels might be given to these organs unavoidably. Certainly long-term radiotherapy related toxicities are significantly associated with the dose and volume irradiating the normal organs at risk. Relying on the techniques of modern conformal radiotherapy and the contemporary strategy of multimodality therapy, the dose and volume irradiating the heart and lung were considerably reduced. Therefore, objective tools including heart echocardiography and lung function test will be utilized in this prospective study to evaluate and monitor mainly the patients diagnosed as malignant lymphoma who are recommended to receive mediastinal radiotherapy in the era of modern treatment strategy and techniques.

The participants potentially included in the current study are mainly lymphoma patients with mediastinal malignant lymphoma or patients whose radiation therapy field essentially encompasses anterior mediastinum. Patients are prospectively enrolled in this study after physicians' clinical judgement. After signing the consent form, the recruited patient will receive comprehensive pre-radiotherapy evaluations, including cardiac echocardiography, laboratory tests (BNP, and NT-pro BNP), and lung function tests. Participants who are particularly female patients under the age of 45 will receive pre-radiotherapy breast echocardiography. Radiotherapy treatment planning of both photon and proton respectively will be simulated on Eclipse® treatment planning system. Subsequently participants will receive mediastinal RT within one month after being enrolled in the study. Eligible patients should receive standard multidisciplinary treatment as the tumor board at our institute has suggested. Modern radiotherapy techniques comprise all available modalities in our hospital, including photon or proton beams, intensity-modulated radiotherapy, volumetric modulated arc therapy, image-guidance, and breathing control system. The prescription of treatment field designing and dose scheme will comply with our institutional protocols and updated cancer treatment guidelines. Participants will receive longitudinal follow-up examinations at 3, 6, 9, 12, 18, 24, 36 months after the start of RT course. Standardized examinations include the above mentioned cardiac echocardiography and relevant tests.

It is anticipated that long-term mediastinal RT-related late effects are prospectively and longitudinally surveyed through consistent heart examinations and lung function tests. Long-term effects are expected to be lower with using maturely and widely adopted modern RT techniques. Therapeutic and survival outcomes are expected to be satisfactory, achieving the international level in this prospective observational study focusing on mainly lymphoma patients with mediastinal involvement who are suggested and scheduled to receive mediastinal RT as part of the combined modality treatment.

This study aims to standardize the application of clinical examinations including cardiac echocardiography, lung function tests, and relevant laboratory tests as part of objective tools for monitoring patients' cardiac and pulmonary functions after receiving mediastinal RT. Therefore, it is expected that the risk factors of predisposing patients to develop cardiac toxicities after chemoradiation particularly including mediastinal RT will be explored and identified. In addition objectivity of BNP (or NT-pro BNP) will also be verified in combination with the objective measurement and findings obtained from cardiac echocardiography. It is anticipated that our study would be an important and leading one that integrates radiation oncology, hematology, cardiology, and pulmonology into prospective and longitudinal cardiopulmonary surveillance carried out for mainly malignant lymphoma patients undergoing mediastinal RT in this era of modern chemoradiation.

Lymphoma Patients Undergoing Mediastinal Radiotherapy in the Era of Modern Chemoradiation

A Prospective Observational Study With Longitudinal Cardiopulmonary Surveillance in Lymphoma Patients Undergoing Mediastinal Radiotherapy in the Era of Modern Chemoradiation

The outcome assessed by cardiac echocardiography. Our study use the standard imaging modality -cardiac echocardiography

The outcome assessed by plasma concentrations of BNP and NT-proBNP

The outcome assessed by lung function test. The lung function tests contain following four tests: "Determination of F. R. C" \& "Diffusion capacity rate" \& "Screening sporometry before \& after B. D." and "Simple bronchodilator test".

The outcomes assessed by echocardiography

Overall survival time, indicated by the time from the date of recruitment to the date of expiring

Chang Gung Memorial Hospital

cardiac evaluation (by either transthoracic echocardiography or MUGA) every 3 months

cardiac evaluation (by either transthoracic echocardiography or MUGA) every 4 months

LVEF 3 month

LVEF 4 month

Olexiy Aseyey, MD

Several large adjuvant trastuzumab trials have demonstrated improved overall survival, in participants with early stage breast cancer, with a 33% decrease in risk of death. However, retrospective analyses of participant outcomes in these trials have demonstrated increased risk of cardiotoxicity (i.e damage to the heart) in a small number of patients (4-8%).

At this time, investigators are unable to predict which participants are at increased risk of cardiac-related treatment complications. Currently all patients receive regular cardiac imaging throughout their one year of trastuzumab treatment.

At this time, the optimal monitoring schedule for trastuzumab-related cardiotoxicity remains unknown, and several published consensus guidelines are currently in use as "standard of care.

An Integrated Consent Model Study to Compare Two Standard of Care Schedules for Monitoring Cardiac Function in Patients Receiving Trastuzumab for Early Stage Breast Cancer

Changes in LVEF results compared to baseline (by echocardiography or MUGA) throughout the course of trastuzumab based therapy

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Reporting, Evaluating, Preventing and Treating the Cardiotoxicity Induced by Anticancer Drugs During a Specific Cardio-oncology Consult and Follow up in Routine Care	NCT03882580	Cardiovascular ... Cardiovascular ... Cardiac Complic... Oncologic Compl... Cardiac Insuffi... Metabolic Disor... Vascular Disord... Cardiac Disorde...	Anti-Cancer Age...	18 Years -	Groupe Hospitalier Pitie-Salpetriere
Evaluating 6-months of HER2-targeted Therapy in Patients With HER2 Positive Early-stage Breast Cancer That Achieve a Pathological Complete Response to Neoadjuvant Systemic Therapy	NCT04928261	Breast Cancer	Trastuzumab	18 Years -	Ottawa Hospital Research Institute
Role of Silymarin in Chemotherapy Toxicity and Cognition Improvement in Breast Cancer Patients	NCT05595109	Breast Cancer Peripheral Neur... Cardiac Toxicit... Hepatic Toxicit... Cognitive Impai...	Silymarin Placebo	18 Years -	Tanta University
Lymphoma Patients Undergoing Mediastinal Radiotherapy in the Era of Modern Chemoradiation	NCT03969693	Mediastinal Lym... Hodgkin Lymphom... Non Hodgkin Lym...	Standard treatm...	15 Years - 80 Years	Chang Gung Memorial Hospital
Lymphoma Patients Undergoing Mediastinal Radiotherapy in the Era of Modern Chemoradiation	NCT03969693	Mediastinal Lym... Hodgkin Lymphom... Non Hodgkin Lym...	Standard treatm...	15 Years - 80 Years	Chang Gung Memorial Hospital
Evaluating 6-months of HER2-targeted Therapy in Patients With HER2 Positive Early-stage Breast Cancer That Achieve a Pathological Complete Response to Neoadjuvant Systemic Therapy	NCT04928261	Breast Cancer	Trastuzumab	18 Years -	Ottawa Hospital Research Institute
Reporting, Evaluating, Preventing and Treating the Cardiotoxicity Induced by Anticancer Drugs During a Specific Cardio-oncology Consult and Follow up in Routine Care	NCT03882580	Cardiovascular ... Cardiovascular ... Cardiac Complic... Oncologic Compl... Cardiac Insuffi... Metabolic Disor... Vascular Disord... Cardiac Disorde...	Anti-Cancer Age...	18 Years -	Groupe Hospitalier Pitie-Salpetriere
An Integrated Consent Model Study to Compare Two Standard of Care Schedules for Monitoring Cardiac Function in Patients Receiving Trastuzumab for Early Stage Breast Cancer	NCT02696707	Breast Cancer	LVEF 3 month LVEF 4 month	18 Years -	Ottawa Hospital Research Institute

Spots Global Cancer Trial Database for cardiac toxicities